Halogenated pyrimidine nucleosides are clinically effective radiosensitizers. These nucleosides replace thymidine in the DNA of cycling cells rendering them more sensitive to radiation compared to cells not containing halogenated pyrimidines. Kinsella, et al. Int. J. Radiation Oncology Biol. Phys., vol. 10, pp. 1399-1406 (1984), and Mitchell et al., Int. J. Radiation Oncology Biol. Phys., Vol. 12, pp. 1513-1518 (1986) describe the use of these radiosensitizers in radiobiology and radiotherapy.
Kinsella, et al. review the basic strategy for using halogenated pyrimidine analogs bromodeoxyuridine and iododeoxyuridine as radiosensitizers, and describe clinical trials using these compounds. Recent clinical trials using continuous intravenous administration show that systemic toxicity limits the infusion rate and duration of infusion. The authors conclude that therapeutic gain must be improved by limiting systemic toxicity and increasing tumor cell incorporation.
Mitchell, et al. review halogenated pyrimidine non-hypoxic cell radiosensitizers incorporated into cellular DNA for X-ray sensitization. Recent studies in high-grade glioblastoma and large unresectable sarcoma tumor sites show the compounds have little impact on long-term survival (Kinsella et al., J. Clin. Oncol. vol. 2 pp. 1144-1150 (1984) and Kinsella et al. Int. J. Radiat. Oncol. Biol. Phys. vol. 10, pp. 69-76 (1984)).
Previous ester prodrugs have depended on enzymatic hydrolysis to give useful rates of conversion of prodrugs to drugs. There is great variability in esterase concentrations between individuals and tumor drug levels may be inconsistent and unpredictable.
It is a purpose of the invention to provide halogenated pyrimidine nucelosides which replace DNA thymidine bases with halogenated bases to an extent sufficient to deliver a high degree of radiosensitization.
It is also a purpose of the invention to provide prodrugs that undergo transformation by a non-enzymatic mechanism and produce more predictable and consistent tumor levels of drug.
It is also a purpose of the invention to provide halogenated pyrimidine nucleosides which can be safely delivered to malignant cells at high concentration.
It is also a purpose of the invention to provide safe methods for replacing DNA thymidine base with halogenated bases, thereby delivering a high degree of radiosensitization.